Regina Tardanico

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Renal angiomyolipoma with epithelioid sarcomatous transformation and metastases: demonstration of the same genetic defects in the primary and metastatic lesions.

Angiomyolipoma (AML) is a benign neoplasm that occurs either sporadically or in patients with tuberous sclerosis complex (TSC) and shows frequent allelic losses at chromosome arm 16p. It has been suggested recently that the melanogenesis marker-positive perivascular epithelioid cell (PEC) has been found consistently in AML. The authors report a 50-year-old woman without evidence of TSC affected by classic renal AML containing an area composed of atypical epithelioid cells with the same morphoimmunophenotypic characters of PEC. After 7 years from surgical removal of the lesion, the patient developed a local recurrence and successive lung and abdominal metastases that showed morphologic and immunohistochemical features overlapping those of the epithelioid area of the previously removed AML. Genetic analysis showed that the classic AML and its epithelioid area as well as the pulmonary and abdominal metastases shared the same allelic loss on chromosome arm 16p. Based on these findings, the authors view this case as evidence of a malignant transformation of a classic AML with morphologic, immunophenotypic, and genetic demonstration of its clonal origin.

Parvalbumin Is Constantly Expressed in Chromophobe Renal Carcinoma

Chromophobe renal carcinoma is composed of neoplastic cell showing several features similar to those found in the intercalated cells of the collecting ducts. Because the distal nephron expresses calcium-binding proteins playing a role in calcium homeostasis, we reasoned that these proteins could be expressed by chromophobe carcinoma and therefore represent a diagnostic marker. We studied the immunohistochemical expression of different calcium-binding proteins (parvalbumin, calbindin-D28K, and calretinin) in 140 renal tumors, including 75 conventional (clear cell) carcinomas, 32 chromophobe carcinomas, 17 papillary renal cell carcinomas, and 16 oncocytomas. Parvalbumin was strongly positive in all primary chromophobe carcinomas and in one pancreatic metastasis; it was positive in 11 of 16 oncocytomas and absent in conventional (clear cell) and papillary renal cell carcinomas, either primary or metastatic. Calbindin-D28K and calretinin were negative in all tumors, with the exception of two chromophobe carcinomas, four oncocytomas, and two papillary renal cell carcinomas showing inconspicuous calretinin expression. Our data demonstrate that parvalbumin may be a suitable marker for distinguishing primary and metastatic chromophobe carcinoma from conventional (clear cell) and papillary renal cell carcinoma. Moreover, they suggest a relationship between chromophobe renal carcinoma and renal oncocytoma and indicate that chromophobe carcinoma exhibits differentiation toward the collecting-duct phenotype.

Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage

Recent evidences suggest a significant role of Plasmacytoid dendritic cells (PDC) role in the pathogenesis of lupus erythematosus (LE) via production of type I IFN. Taking advantage on the availability of multiple reagents (CD123, BDCA2, and CD2ap) specifically recognizing PDC on fixed tissues, we investigated the occurrence of PDC in a cohort of 74 LE patients. The large majority of LE biopsies (67/74; 90.5%) showed cutaneous infiltration of PDC. PDC were more frequently observed (96.4 vs 72.2) and numerous in cutaneous LE compared to systemic LE (SLE) and correlated with the density of the inflammatory infiltrate (r=0.40; p<0.001). PDC reduction in SLE might be related to a broader tissue distribution of this cellular population, as indicated by their occurrence in kidneys in 11 out of 24 (45.8%) cases studied. The distribution of cutaneous PDC showed two distinct patterns. More commonly, PDC were observed within perivascular inflammatory nodules in the dermis, associated with CD208+ mature DC and T-bet+ cells [D-PDC]. A second component was observed along the dermal-epithelial junction [J-PDC], in association with cytotoxic T-cells in areas of severe epithelial damage. Notably, chemerin reactivity was observed in 64% of LE biopsies on endothelial cells and in the granular layer keratinocytes. Cutaneous PDC in LE strongly produced type I IFN, as indicated by the diffuse MxA expression, and the cytotoxic molecule granzyme B. This study confirms cutaneous PDC infiltration as hallmark of LE. The topographical segregation in D-PDC and J-PDC suggests a novel view of the role of these cells in skin autoimmunity.

Renal disease in adults with TSC2/PKD1 contiguous gene syndrome

The most common renal lesions of tuberous sclerosis complex, an autosomal-dominant syndrome resulting from losses of TSC1 (9q34) or TSC2 (16p13.3), are renal cysts and angiomyolipomas. Epithelial neoplasms are less common. The TSC2 gene lies adjacent to PKD1, the major gene responsible for autosomal-dominant polycystic kidney disease. Recently, a deletion mutation disrupting both TSC2 and PKD1 has been described in young children with tuberous sclerosis complex with severe renal cystic disease. This disease has been termed the TSC2/PKD1 contiguous gene syndrome. We describe the lesions in the resected kidneys of two adults with TSC2/PDK1 contiguous gene syndrome, at the time of the nephrectomies: a 31-year-old man and his 44-year-old mother. The four kidneys were enlarged reniform masses composed of cysts lined by flattened, cuboidal, or, infrequently, large deeply eosinophilic epithelial cells. The kidneys also contained numerous classic angiomyolipomas and rare intraglomerular microlesions. In the son the largest tumor was a monotypic epithelioid angiomyolipoma. In the wall of his left renal pelvis there was a plaque-shaped, HMB-45-positive localized lesion of lymphangioleiomyomatosis. This is the first description of the renal lesions in adults with genetically confirmed TSC2/PDK1 contiguous gene syndrome. The pathologic findings highlight the importance of thorough sampling for histology in polycystic kidney diseases and indicate that the observation of an angiomyolipoma in biopsy material from patients with enlarged cystic kidneys should suggest the diagnosis of TSC2/PKD1 contiguous gene syndrome, even in cases without ultrasonographic and macroscopic evidence of angiomyolipoma.

Association between Silica Exposure and Necrotizing Crescentic Glomerulonephritis with p-ANCA and anti-MPO Antibodies: A Hospital-Based Case-Control Study

A hospital-based case-control study was carried out to investigate the association between ANCA positive rapidly progressive glomerulonephritis (RPGN) and occupational exposure to silica dust. All ANCA positive male patients admitted to the Department of Nephrology of the University of Brescia between 1987 and 1992 were enrolled in the study as cases. The controls were pts of the same age, admitted at the Department immediately before or after the cases, affected by other renal diseases. Seven of the 16 cases and one of the 32 controls, had a positive history for jobs exposing to silica dust (relative risk 14; 95% C.I.: 1.7-113.8, p < 0.001). ANCA pattern was p-ANCA with anti-MPO antibodies in 6/7 of exposed pts. The review of renal histology showed a distinctive glomerular lesion consisting in peripheral nodular areas of glomerular sclerosis, in addition to the crescentic necrotizing glomerulonephritis, in 3/6 silica exposed pts, but in none of the unexposed pts.

Renal Apolipoprotein A-I Amyloidosis: A Rare and Usually Ignored Cause of Hereditary Tubulointerstitial Nephritis

Apolipoprotein A-I amyloidosis is a rare, late-onset, autosomal dominant condition characterized by systemic deposition of amyloid in tissues, the major clinical problems being related to renal, hepatic, and cardiac involvement. Described is the clinical and histologic picture of renal involvement as a result of apolipoprotein A-I amyloidosis in five families of Italian ancestry. In all of the affected family members, the disease was caused by the Leu75Pro heterozygous mutation in exon 4 of apolipoprotein A-I gene, as demonstrated by direct sequencing and RFLP analysis. Immunohistochemistry confirmed that amyloid deposits were specifically stained with an anti-apolipoprotein A-I antibody. The clinical phenotype was mainly characterized by a variable combination of kidney and liver disturbance. The occurrence of renal involvement seemed to be almost universal, although its severity varied greatly ranging from subclinical organ damage to overt, slowly progressive renal dysfunction. The renal presentation was consistent with a tubulointerstitial disease, as suggested by the findings of defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria. Histology confirmed tubulointerstitial nephritis. Surprising, amyloid was restricted to nonglomerular regions and limited to the renal medulla. This location of apolipoprotein A-I amyloid differs sharply from other systemic amyloidoses that are mainly characterized by glomerular and vascular deposits. The tubulointerstitial nephritis as a result of hereditary apolipoprotein A-I amyloidosis is a rare disease and a challenging diagnosis to recognize. Patients who present with familial tubulointerstitial nephritis associated with liver disease require a high index of suspicion for apolipoprotein A-I amyloidosis.

Claudin 4 identifies a wide spectrum of epithelial neoplasms and represents a very useful marker for carcinoma versus mesothelioma diagnosis in pleural and peritoneal biopsies and effusions

We evaluated the usefulness of the tight-junction associated protein Claudin 4 (CL-4) in the diagnosis of mesothelioma and mimickers, analyzing biopsies from 454 tumors, including 82 mesotheliomas, 336 carcinomas of different origin (278 primary, 58 metastatic to serosae), 36 nonepithelial spindle cell neoplasms, as well as 97 cytological samples from reactive effusions (12), mesothelioma (23) and metastatic carcinomas (62). CL-4 was consistently negative in normal and reactive mesothelium, as well as in all 82 mesotheliomas. In contrast, strong reactivity was found in 57/58 serosal metastasis, and in 245/278 primary carcinomas, with uppermost expression (150/153) in those most frequently involved in the differential with mesothelioma (lung, breast, gastrointestinal tract, pancreas, ovary, primary serous papillary carcinoma of peritoneum). On effusions, reactive and neoplastic mesothelial cells were regularly negative, while metastatic tumor cells stained positively in 60/62 (96.8%) cases. Among spindle cell neoplasms, only 2/9 biphasic synovial sarcomas and 4/4 follicular dendritic cell sarcomas stained positively. Results indicate that CL-4 reacts with the majority of epithelial neoplasms that often metastasize to serous membranes, representing a pancarcinoma marker with extremely high sensitivity and specificity. CL-4 may be considered a primary immunohistochemical reagent to rule out the diagnosis of mesothelioma.

Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis.

The objective of the current study was to identify independent clinical and pathologic variables that were predictive of lymph node involvement in patients with squamous cell carcinoma of the penis in a multicenter series with the intent to select patients who were suitable to undergo immediate inguinal lymphadenectomy.

Glomerular Autoimmune Multicomponents of Human Lupus Nephritis In Vivo: α-Enolase and Annexin AI

Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against α-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of α-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-α-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-α-enolase/low anti-annexin AI IgG2 and patients with low anti-α-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti-α-enolase IgG2 recognized specific epitopes of α-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human α-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against α-enolase and annexin AI predominate in the glomerulus and can be detected in serum.